Glucocorticoid is a hormone inducing metabolic disorders such as hyperglycemia, insulin resistance, obesity, hyperlipemia and hypertension and is not only produced from the adrenal gland but also converted from an inactive form into an active form at a tissue level to act via its receptor.
11β-Hydroxysteroid dehydrogenase (11β-HSD) is an enzyme catalyzing the conversion and the presence of two sub-types is known. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme catalyzing the conversion of the inactive form into the active form and is highly expressed in liver and 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) is an enzyme catalyzing the conversion of the active form into the inactive form and is highly expressed in kidney. As a relation between 11β-HSD1 and metabolic diseases, it has been known that activity of 11β-HSD1 is increased in the adipose tissue of a corpulent person (Non-Patent Document 1) and it has been reported that 11β-HSD1 activity shows high correlation with BMI that is an index of the degree of obesity, HOMA-IR that is an index of insulin resistance, and a fasting blood-glucose level (Non-Patent Document 2). Moreover, in a transgenic mouse wherein 11β-HSD1 is overexpressed in an adipose tissue-selective manner, it has been reported that glucocorticoid in the adipose tissue increases and the mouse exhibits insulin resistance, visceral fat-type obesity, hyperlipemia, and hypertension (Non-Patent Documents 3 and 4). In addition, it has been reported that 11β-HSD1 knockout mouse shows improvement in glucose tolerance, decrease in blood triglyceride level and increase in HDL-cholesterol (Non-Patent Document 5).
From the above, it is expected that 11β-HSD1-selective inhibitor suppresses the glucocorticoid action in tissue through inhibition of the conversion into active-form glucocorticoid and, as a result, remedies the metabolic disorders such as hyperglycemia, insulin resistance, obesity, hyperlipidemia and hypertension which are induced by glucocorticoid.
Furthermore, it has been reported that a non-selective 11β-HSD inhibiting agent, carbenoxolone improves decrease in insulin secretion induced by addition of inactive glucocorticoid in murine pancreatic β-cell (Non-Patent Document 6) and thus there is a possibility that a 11β-HSD1 inhibiting agent may not only improve insulin resistance but also remedy hyperglycemia though promotion of insulin secretion.
As the other diseases in which 11β-HSD1 participates, osteoporosis (Non-Patent Document 7), glaucoma (Non-Patent Document 8), and decrease in cognitive function (Non-Patent Document 9) are known, and hence effects of improvement thereof are also expected.
With regard to compounds having an 11β-HSD1 inhibitory action, the following Patent Documents 1 to 8 are known.
Patent Document 1 has reported a triazole derivative represented by the formula (A). However, the derivative is different from the compound of the current invention in a point that the derivative does not contain parts corresponding to A and B of the compound of the invention:
wherein R1 represents optionally substituted adamantyl, X represents CH2 or a single bond, Z represents S or a single bond (see the document for the other symbols).
Patent Document 2 has reported a triazole derivative represented by the formula (B). However, the derivative is different from the compound of the current invention in a point that the ring attached to the triazole ring is bicyclo[2.2.2]octane:
(see the document for the symbols in the formula).
Patent Documents 3 and 4 have reported a triazole derivative represented by the formula (C). However, the derivative is different from the compound of the current invention in a point that the optionally substituted phenyl ring is attached to the triazole ring through one carbon atom:
wherein R3 represents a group selected from each optionally substituted C1-14 alkyl, C2-10 alkenyl, SC1-6 alkyl, C6-10 aryl, heterocycle and heteroaryl in the case that R2 and R3 are separated from each other; A represents halo or each optionally substituted C1-6 alkyl, OC1-6 alkyl or phenyl and B represents H, halo or each optionally substituted C1-6 alkyl, OC1-6 alkyl, SC1-6 alkyl, C2-6 alkenyl, phenyl or naphthyl in the case that A and B are separated from each other (see the document for the other symbols).
Patent Document 5 has reported a triazole derivative represented by the formula (D). However, any compounds having substituents at the parts corresponding to A and B of the compound of the current invention are not disclosed as Examples:
wherein X represents O or S, R1 represents each optionally substituted C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, or the like, R3 represents each optionally substituted C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, heteroarylC1-C6 alkyl, arylR8C1-C6 alkyl, or heteroarylR8C1-C6 alkyl; R8 represents NR10, C(═O)R10 or SOnR10 (see the document for the other symbols).
Patent Document 6 published after the priority date of the present application has reported a triazole derivative represented by the formula (E). However, compounds wherein a ring is directly attached to the triazole ring are only disclosed as Examples:
wherein R1 represents C5-C10 cycloalkyl, C5-C10 heterocycloalkyl, aryl, heteroaryl, arylC1-C6 alkyl, or heteroarylC1-C6 alkyl, or the like (see the document for the other symbols).
Patent Document 7 published after the priority date of the present application has reported a triazole derivative represented by the formula (F). However, Y corresponding to A and B of the compound of the current invention is limited to a ring structure:
(see the document for the other symbols in the formula).
Patent Document 8 published after the priority date of the present application has reported a wide variety of compounds represented by the formula (G). However, as compounds having substituents corresponding to A and B of the compound of the invention, compounds wherein the part corresponding to R1 of the compound of the invention is aryl are only disclosed as Examples:
wherein R1 represents a hydrogen atom or an optionally substituted cyclic group, R2 represents an optionally substituted cyclic group, Ar represents an optionally substituted 5- or 6-membered aromatic heterocycle, and L1 and L2 are the same or different and each represents (1) a bonding hand, (2) an optionally substituted hydrocarbon group, or the like.    Non-Patent Document 1: Rask E., et al., “The Journal of Clinical Endocrinology & Metabolism”, (USA), 2001, Vol. 86, pp. 1418-1421    Non-Patent Document 2: Lindsay R. S., et al., “The Journal of Clinical Endocrinology & Metabolism”, 2003, Vol. 88, pp. 2738-2744    Non-Patent Document 3: Masuzaki H., et al., “Science”, (USA), 2001, Vol. 294, pp. 2166-2170    Non-Patent Document 4: Masuzaki H., et al., “The Journal of Clinical Investigation”, (USA), 2003, Vol. 112, pp. 83-90    Non-Patent Document 5: Morton N. M., et al., “The Journal of Biological Chemistry”, (USA), 2001, Vol. 276, pp. 41293-41300    Non-Patent Document 6: Davani B., et al., “The Journal of Biological Chemistry”, (USA), 2000, Vol. 275, pp. 34841-34844    Non-Patent Document 7: Cooper M. S., et al., “Bone”, (USA), 2000, Vol. 27, pp. 375-381    Non-Patent Document 8: Rauz S., et al., “Investigative Opthalmology & Visual Science”, (USA), 2001, Vol. 42, pp. 2037-2042    Non-Patent Document 9: Sandeep T. C., et al., “Proceedings of the National Academy of Science”, (USA), 2004, Vol. 101, pp. 6734-6739    Patent Document 1: WO03/65983 pamphlet    Patent Document 2: US-A-2004/133011 specification    Patent Document 3: WO03/104207 pamphlet    Patent Document 4: WO03/104208 pamphlet    Patent Document 5: WO04/089367 pamphlet    Patent Document 6: WO04/089380 pamphlet    Patent Document 7: WO05/044192 pamphlet    Patent Document 8: JP-A-2005/170939 publication